The principal goal of this research program is to develop a practical synthetic approach to the spongipyrans, a family of architecturally unique bisspiroketal macrolides, which possess extraordinary antitumor activities. Building upon the progress of the 01-03 years, we achieved the total syntheses of both (+)- spongistatin 1 and 2 in the 04-07 years; the former proved to be the shortest synthesis of a spongistatin reported to date, with a longest linear sequence of 29 steps (other published sequences are ca. greater than or equal too 32 steps). Equally important, we have developed a highly efficient (22 steps, 4% overall yield), second-generation synthesis of the requisite advanced ABCD aldehyde, capable of producing gram quantities (vide infra), which when combined with an equally viable synthesis of the advanced EF Wittig salt, will permit construction of at least one gram of totally synthetic spongistatin 1 for pre-clinical development. The specific aims (A-E) for the next four years are: (A) to complete a highly efficient third-generation synthesis of spongistatin 1 capable of delivering a minimum of one gram, in order to make this important antitumor agent available for pre-clinical evaluation; (B) to provide advanced intermediates for in depth structure-activity studies; (C) to design and synthesize, guided by the structural activity results, less complex analogs possessing significant antitumor activity; and (D) to prepare photo-affinity, fluorescent and radiolabels to define both the site and molecular mechanism of action of these important antitumor agents. Notwithstanding the enormity of this challenge, we are convinced that the synthetic plan described herein will prove superior to isolation as a practical and environmentally sound source of this exciting and immensely important anticancer agent. In the area of new synthetic methods, the Specific Aims for the next four years will include: (E) the development of new bifunctional reagents based on the Brook rearrangement to construct a variety of structurally complex structures via multicomponent one-flask reactions.